期刊
CANCER CELL
卷 29, 期 2, 页码 159-172出版社
CELL PRESS
DOI: 10.1016/j.ccell.2016.01.002
关键词
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资金
- Rally Foundation for Childhood Cancer Research
- The Truth 365
- Alex's Lemonade Stand Innovation grant
- Wipe out Kids Cancer research grant
- VCU Massey Cancer Center Pilot Project Application grant
- Wellcome Trust [102696]
- George and Lavina Blick Research Fund
Fewer than half of children with high-risk neuroblastoma survive. Many of these tumors harbor high-level amplification of MYCN, which correlates with poor disease outcome. Using data from our large drug screen we predicted, and subsequently demonstrated, that MYCN-amplified neuroblastomas are sensitive to the BCL-2 inhibitor ABT-199. This sensitivity occurs in part through low anti-apoptotic BCL-xL expression, high pro-apoptotic NOXA expression, and paradoxical, MYCN-driven upregulation of NOXA. Screening for enhancers of ABT-199 sensitivity in MYCN-amplified neuroblastomas, we demonstrate that the Aurora Kinase A inhibitor MLN8237 combines with ABT-199 to induce widespread apoptosis. In diverse models of MYCN-amplified neuroblastoma, including a patient-derived xenograft model, this combination uniformly induced tumor shrinkage, and in multiple instances led to complete tumor regression.
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